Fatty acid synthase (FASN) is a key enzyme for the synthesis of long-chain fatty acids from acetyl-coenzyme A (CoA) and malonyl-CoA that uses reduced nicotinamide adenine dinucleotidephosphate as a cofactor. FASN is minimally expressed in most normal human tissues except the liver and adipose tissue, where it is expressed at high levels.
Since FASN expression is markedly increased in several human cancers compared with the corresponding normal tissue, and FASN overexpression in tumors has been associated with a poor prognosis, FASN inhibitors have long been viewed as potential therapeutics for the treatment of cancer. FASN inhibitors have also shown promise in the treatment of other FASN-mediated diseases, disorders or conditions, such as obesity, lack of appetite control and inflammatory conditions.
Furthermore, FASN has been identified as a target for treatment of microbial infections. In particular, it was reported that fatty acid synthesis or the level of fatty acid is critical in viral pathogenesis. For example, it was reported that the formation of a novel vesicular compartment (i.e., remodeled golgi apparatus), on the surface of which viral RNA replication takes place, requires fatty acid biosynthesis. (See Cherry et al., PLoS Pathogens, 2(10): e102 (2006)). In addition, fatty acid biosynthesis has been identified as a target for anti-viral therapy using a metabolic profiling of the hosts upon viral infection. (See Munger et al., Nature Biotechnology, 26: 1179-1186 (2008). It was also reported that inhibition of fatty acid biosynthesis (e.g., inhibition of fatty acid synthase) results in reduced replication of human cytomegalomous virus (HCMV) and influenza A viruses. (Id.).
Reports establishing FASN as a valid target for the treatment of viral infections are available for various viruses. For example, the role of FASN has been implicated in the pathogenesis of an enveloped virus such as human cytomegalomous virus (HCMV), influenza A and Hepatitis C (HCV). (See Munger et al., Nature Biotechnology, 26: 1179-1186 (2008); Syed et al., Trends in Endocrinology and Metabolism, 21: 33-40 (2009); Sakamoto et al., Nature Chemical Biology, 1: 333-337 (2005); Yang et al., Hepatology, 48: 1396-1403 (2008)). With regard to HCV, it was reported that an elevated level of fatty acid biosynthesis enzymes, including FASN, contributes to liver steatosis, leading to cirrhosis and hepatocellular carcinoma, upon HCV infection. (Fukusawa et al., Biol. Pharm. Bull., 29(9): 1958-1961 (2006)). HCV replication was reported to be regulated by, among others, fatty acid biosynthesis. (Kapadia et al., Proc. Natl. Acad. Sci., 102(7): 2561-2566 (2005)). Other reports establishing FASN as a potential host-target against HCV have also been published. (See, e.g., Hepatology, 48: 1396 (2008); Trends Endocrine Metabol., 21: 33 (2010); and Virology, 394: 130 (2009)).
With regard to other various viruses, it was reported that the FASN expression is increased in the cells infected by coxsackievirus B3 (CVB3), a picornavirus, and the replication of CVB3 is blocked by FASN inhibitors. (See Rassmann et al., Antiviral Research, 76: 150-158 (2007)). FASN was reported to be important in lytic viral replication of Epstein-Barr virus (EBV), and it was suggested that FASN inhibition can be a novel approach for blocking the EBV replication. (Li et al., Journal of Virology, 78(8): 4197-4206 (2004)). The role of FASN in the replication of dengue virus has also been implicated. (See, e.g., Heaton et al., Proc. Natl. Acad. Sci., 107(40): 17345-17350 (2010); and Samsa et al., PLoS Pathegens, 5(10): e1000632 (2009)).
Moreover, aside from being a potential target for anti-viral therapy, the role of FASN has also been implicated in diabetes or regulation of the general wellness of the liver. (See, e.g., Wu et al., PNAS Early Edition, www.pnas.org/cgi/doi/10.1073/pnas.1002588108 (2011)). Thus, there is a need for effective inhibitors of FASN, which can be potentially used as therapies for microbial infections, including, but not limited to viral infections, or other diseases and disorders.